USE OF CCK-B RECEPTOR ANTAGONISTS FOR THE TREATMENT OF SLEEP DISORDERS

Description

[0001] The present invention relates to the use of CCK-B antagonists in the manufacture of a medicament for the treatment of sleep disorders.

[0002] Cholecystokinins (CCK) and gastrin are structurally related peptides which exist in gastrointestinal tissue and in the central nervous system. Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form, its carboxyl terminal octapeptide, CCK-8 (also a naturally occurring neuropeptide), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14- amino acid forms, with the minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH₂ (CCK-4) which is the common structural element shared by both CCK and gastrin.

[0003] CCK and gastrin are gastrointestinal hormones and neurotransmitters in the neural and peripheral systems and perform their respective biological roles by binding to particular receptors located at various sites throughout the body. There are at least two subtypes of cholecystokinin receptors termed CCK-A and CCK-B and both are found in the periphery and in the central nervous system.

[0004] The CCK-A receptor, commonly referred to as the "peripheral-type" receptor, is primarily found in the pancreas, gallbladder, ileum, pyloric sphincter and on vagal afferent nerve fibers. Type-A CCK receptors are also found in the brain in discrete regions and serve to provide a number of CNS effects. Due to the ability of CCK-8 and Type-A CCK-selective agonists to suppress food intake in several animal species, considerable interest has been generated toward the development of new substances which function as Type-A receptor-selective CCK agonists in order to serve as anorectic agents.

[0005] The CCK-B or gastrin receptors are found in peripheral neurons, gastrointestinal smooth muscle and gastrointestinal mucosa, most notably in parietal cells, ECL cells, D cells and chief cells. CCK-B receptors also predominate in the brain and have been implicated in the regulation of anxiety, arousal and the action of neuroleptic agents.

[0006] Makovec. F. Drugs of the Future Vol 18 (10) pp919-931, 1993 teaches that compounds which exhibit an antagonist activity at the CCK-B/gastrin receptor have been found in a range of compounds covering a variety of structural types, including amino acid derivatives, benzodiazepines dipeptoids and pyrazolidinones. Information is also provided about CCK-receptor selectivity for compounds within these classes and potential uses thereof.

[0007] Sleep disorders are the disturbances of sleep that affect the ability to fall and or stay asleep, which involve sleeping too much or result in abnormal behaviour associated with sleep. There are two types of sleep which cyclical and are marked by characteristic electro-encephalograms (EEG) and other changes including eye movements. The first phase of sleep which in normal sleep accounts for 75-80% of total sleep time is referred to as the non-rapid-eye-movement (NREM) type and this is characterised by slow waves on the EEG. The second sleep type (REM-rapid eye movement) which follows NREM is characterised by EEG low voltage fast activity and occurs 5 to 6 times during a normal night's sleep. In sleep disorders the balance of the two types of sleep is disturbed.

[0008] We have now found compounds which exhibit an antagonist activity at the CCK-B receptor influence sleep patterns and are therefore useful for the treatment of sleep disorders.

[0009] Thus the present invention provides for the use of a compound having an antagonist activity at the CCK-B receptor in the manufacture of a medicament for the treatment of sleep disorders.

[0010] Examples of suitable CCK-B antagonists for use in the treatment of sleep disorders includes the 1,4-benzodiazepine derivatives having CCK-B antagonist activity described in EPA 167919, EPA 284256, EPA 434360, EPA 434364, EPA 434369, EPA 514125, EPA 51426, EPA 514133, EPA 508796, EPA 508797, EPA 508798, EPA 508799, EPA 523845, EPA 523846, EPA 559170, EPA 549039, WO 9211246, WO 9308175, WO 9307131, WO 9317011, WO 9319053, WO 9308175, WO 9413648 WO 9403437. Within the 1,4 benzodiazepine derivative disclosed above a particularly useful class of CCK-B antagonists include that represented by the general formula (I).

and N-oxides thereof and pharmaceutically acceptable salts thereof wherein R₁ represents C_1-6 alkyl (optionally substituted by hydroxyl C_1-4 alkoxy, COR₄, CONR₅R₆ or C_3-7 cycloalkyl) or C_3-7 cycloalkyl;

R₄ represents C_1-6 alkoxy or optionally substituted phenyl;

R₅ is methyl or ethyl and R₆ is phenyl or R₅ and R₆ together form a C₄-C₆ alkylene chain, which may be substitued by 1 or 2 alkyl groups;

R₂ represents a substituted or unsubstituted phenyl group (wherein the substitutents may be 1 or 2 of halo, C_1-4 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkylthio or R₇ wherein R₇ is hydroxy, C_1-4 alkoxy, CO₂R₈, NR₈R₉, SO₂NR₈COR₁₀, CONR₈SO₂R₁₀, or R₇ represents a tetrazolyl, carboxamidotetrazolyl, 3-trifluoromethyl-1,2-4-triazolyl or 5-oxo-1,2,4 oxadiazolyl group, which groups may be substituted on one of the nitrogen atoms by a C_{1- 4}alkyl group;

R₈ represents hydrogen or a C_1-4 alkyl group;

R₉ independently represents hydrogen or a C_1-4alkyl group or the group SO₂CF₃;

R₁₀ represents C_1-4alkyl;

R₃ represents C_1-6 alkyl, C_3-7 cycloalkyl, phenyl (optionally substituted by halogen), azacycloalkyl or alkyl substituted by an amino, C_1-4 alkylamino, diC_1-4alkylamino, morpholino, pyrrolidino, piperidino, hexamethylene, thiomorpholino or N-methyl piperazino group; X represents hydrogen or halogen.

[0011] Within this class particularly preferred compounds include those wherein R₁ is alkyl e.g. methyl, isopropyl or CH₂COR₄ wherein R⁴ is optionally substituted phenyl or the group CH₂CO NR₅R₆ wherein R₅ is methyl or ethyl and R₆ is an optionally substituted phenyl group or NR₅R₆ represents a pyrrolidino, or piperidino group, which groups may be optionally substituted by one or 2 alkyl groups; and R₃ is alkyl, cycloalkyl, phenyl optionally substituted by fluorine or a group selected from

wherein n is 1 or 2
Examples of particularly suitable compounds from within this class are those wherein X is hydrogen, and R₁ is methyl, R₃ is phenyl and R₂ is 3-methyl phenyl or 3-(5-oxo-1,2,4-oxadiazol-3-yl) phenyl or R₁ is methyl, R₂ is 3-methyl phenyl and R₃ is

or R₁ is isopropyl, R₃ is phenyl and R₂ is 3-(1H-tetrazol-5-yl)phenyl,
or R₁ is CH₂COR₄ wherein R₄ is 2-methylphenyl, R₂ is 3 methylphenyl and R₃ is phenyl

[0012] Further examples of suitable CCK-B antagonists for use in the invention include the 1,5-benzodiazepine derivatives having CCK-B antagonist activity described in WO9314074, WO9314075, O094261491, WO9424151, WO9425444, WO9503299, WO9503284, WO9503285 and WO9425445.

[0013] Within the 1,5-benzodiazepine derivatives described in the above identified patent applications a particularly useful class of CCK-B antagonists for use in this invention are those of general formula (II).

wherein

R₁₁ represents a phenyl, C_3-7cycloalkyl, C_7-11 bridged cycloalkyl or C_1-6alkyl group which alkyl group may be substituted by a hydroxy, phenyl, C_1-6alkoxycarbonyl, C_3-7cycloalkyl, or C_7-11 bridged cycloalkyl group;

R₁₂ represents a phenyl group optionally substituted by 1 or 2 substituents selected from, halogen, C_1-4alkyl, C_1-4alkylthio, cyano, nitro, trifluoromethyl, trifluoromethoxy, (CH₂)_nR₁₄ or O(CH₂)pR₁₄ wherein R₁₄ represents hydroxy, C_{1- 4}alkoxy, CO₂R₁₅ or NR₁₆R₁₇; n is zero or 1; p is an integer from 1 to 4;

R₁₃ represents the group AlkNR₁₈R₁₉ or phenyl optionally substituted by 1 or 2 halogen atom;

R₁₅ represents hydrogen or C_1-4alkyl;

R₁₆ represents hydrogen or C_1-4alkyl;

R₁₇ represents hydrogen, C_1-4alkyl, acyl, or C_2-6alkyl substituted by one or more hydroxy, carboxyl and/or amino groups or R₁₆ and R₁₇ together with the nitrogen atom to which they are attached form a 5-7 saturated heterocyclic ring which contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C_1-4alkyl or hydroxy groups.

R₁₈ and R₁₉ independently represent hydrogen, C_1-4alkyl or C_2-6alkyl substituted by one or more hydroxy, carboxyl and/or amino groups or R₁₈ and R₁₉ together with the nitrogen atom to which they are attached represent a 5-7 saturated heterocyclic ring which may contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C_1-4alkyl or hydroxy groups; Alk represents a straight or branched C_2-6alkylene chain optionally substituted by an hydroxyl group;

Y represents hydrogen or 1 or 2 halogen atoms;

and pharmaceutically acceptable salts and or metabolically labile esters.

[0014] For compounds of formula (II) examples of suitable R₁₁ groups include a C_4-6alkyl e.g. 3-methyl butyl, 3,3-dimethyl butyl, C_3-6 hydroxy alkyl e.g. 2-hydroxypropyl, 2-hydroxy-3- methylbutyl, 2-hydroxy-3,3-dimethylbutyl, C_1-2alkyl substituted by a bridged C_7-10cycloalkyl group e.g. 2-norbornanylmethyl, 5-norbornenylmethyl, 1-adamantylmethyl, alkoxycarbonylalkyl, e.g. methoxycarbonylmethyl or t-butyoxycarbonylmethyl, cyclohexylmethyl, or 2-cyclopentylethyl.

[0015] Conveniently R₁ represents 3-methylbutyl or 1-adamantylmethyl and more particularly 1-adamantylmethyl.

[0016] When R₁₃ is an optionally substituted phenyl group this is conveniently phenyl or 2-fluorophenyl and more particularly phenyl.

[0017] When R₁₃ is the group AlkNR₁₈R₁₉; the group Alk conveniently represents ethylene, propylene or 2-hydroxymethyl-ethylene and more particularly ethylene.

[0018] Examples of suitable NR₁₈R₁₉ groups include amino, dimethylamino, diethylamino, morpholino, pyrrolidino, piperidino or hexamethyleneimino.

[0019] Conveniently R₁₃ represents morpholinoethyl, piperidinoethyl, pyrrolidinoethyl, dimethylaminoethyl, diethylaminoethyl, dimethylamino-propyl or 2-hydroxymethyl-2-aminoethyl or hexamethyleneiminoethyl. More preferably R₁₃ represents morpholinoethyl.

[0020] Y conveniently represents fluorine or chlorine or more particularly hydrogen.

[0021] A preferred group of compounds of formula (II) for use in the invention are those wherein R₁₁ represents 1-adamantylmethyl R₁₂ is phenyl optionally substituted in the meta position by a methyl, methoxy, methylthio, nitro, dimethylamino, ethoxycarbonyl or carbonyl group; R₁₃ is phenyl and Y is hydrogen. Within this group especially preferred compounds are those wherein R₁₂ is phenyl optionally substituted by dimethylamino, ethoxycarbonyl or carboxyl group.

[0022] A further preferred group of compounds of formula (II) for use in the present invention include those wherein R₁₁ is 1-adamantylmethyl, R₁₂ is phenyl optionally substituted by halogen e.g. fluorine or bromine, R₁₃ represents, 2-(4-morpholino)ethyl, 2-(1-piperidino)ethyl, 2-(1-pyrrolidino)ethyl, 2-(dimethylamino)ethyl, 3-(dimethylamino)propyl, 2-hydroxymethyl -2-aminoethyl, 3-aminopropyl, and Y is hydrogen or fluorine.

[0023] A yet further preferred group of compounds of formula (II) for use in the present invention include those wherein R₁₁ is 3-methylbutyl, R₁₂ is phenyl optionally substituted by methyl, methoxy, chlorine, bromine, fluorine, trifluoromethyl, or methoxy, R₁₃ is 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 2-(1-piperidino)ethyl or 2-(4-morpholino)ethyl, Y is hydrogen or fluorine.

[0024] A further preferred group of compounds of formula (II) are those wherein R₁₁ is 1-adamantylmethyl, R₁₃ is phenyl or the fluorophenyl and R₁₂ is phenyl or phenyl substituted by methyl, methoxy, methylthio, nitro, dimethylamino, ethoxycarbonyl or carboxy or R₁₃ represents 2-(4-morpholino)ethyl, 2-(1-piperidino)ethyl, 2-(1-pyrrolidino)ethyl, 2-(dimethylamino)ethyl, 3-(dimethylamino)propyl, 2-hydroxymethyl -2-aminoethyl, 3-aminopropyl, R₁₂ is phenyl or phenyl substituted by methyl, methoxy or flourine, Y is hydrogen or fluorine, and more particularly hydrogen.

[0025] Specific preferred compounds of formula (II) for the treatment of sleep disorders include the specific preferred compounds described in WO9314074, WO9503285 and WO9503284.

[0026] Particularly preferred compounds of formula (II) for use in the treatment of sleep disorders include:

N-phenyl-N'-[2,3,4,5-tetrahydro-2,4-dioxo-1-(1-adamantylmethyl)-5-phenyl-1H-1,5-benzodiazepin-3-yl]urea;

N-[1-(1-Adamantylmethyl)-2,4-dioxo-5-[2-(4-morpholino)ethyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea;

N-1[-(Adamantylmethyl)-2,4,-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-(3-carboxyphenyl)urea;

N-[(1-Adamantylmethyl)-5-[2-(dimethylamino)ethyl]-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea;

and enantiomers and physiologically acceptable salts thereof.

[0027] It will be appreciated that compounds of formulae (I) and (II) possess at least one asymmetric carbon atom (namely the carbon atom occupying the 3-position of the diazepine ring) and the compounds of the invention thus include all stereoisomers and mixtures thereof including the racemates.

[0028] Further examples of CCK-B antagonists for use in the invention include the peptide derivatives described in EPA 4055537, WO 9204045, WO 9204322, WO9204348 and WO 91/3907.

[0029] Conveniently the peptide derivatives with CCK-B antagonist activity for use in the invention include the tryptophan based dipeptoids and in particular;

[1S-[1α,2β,[S*(S*)],4α]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1 -oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl) oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid and salts thereof and

(R-(R*,R*))-4-((2-((3-(1H-indol-3-yl)-2-methyl-2-(( (tricyclo(3.3.1.1,3,7)dec-2-yloxy)carbonyl)amino)propyl) amino)-1-phenylethyl)amino)-4-oxobutanoic acid and salts thereof.

[0030] Yet further examples of CCK-B antagonists for use in the treatment of sleep disorders include those described in WO9507261, WO9503281, EP620221, WO9419322, WO9400421, WO9401421, WO9315059, WO9321172, EP518731, WO9210479, USP53997308, EP655053, WO9505359, WO9419322, WO9406802, WO9426718, WO9294045 and EP46714.

[0031] From within the compounds described therein particularly useful compounds include the 3-phenylureido-azepin-2-ones and 3-phenylureido-benzazepin-2-ones described in WO9315059. From within this class a particularly interesting compound is N-tert butyl 2[3-[3-(3-chlorophenyl)ureido]-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)-benzazepin-1-yr]ethanoic acid amide.

[0032] A further interesting class CCK-B antagonist for use in the invention are the aspartic acid and glutamic acid derivatives described in WO9210479 and WO9507261. Examples of particularly suitable compounds from within this class are spiroglumide and related compounds.

[0033] Preferred CCK-B antagonist for use in the treatment of sleep disorders include

(a) 1,4-benzodiazepines of formula (I) and more particularly the compounds wherein X is hydrogen, R₁ is methyl, R₂ is 3-methylphenyl or 3-(5 oxo-1,2,4-oxadiazol-3-yl) phenyl and R₃ is phenyl; X is hydrogen. R₁ is methyl, R₂ is 3 methylphenyl and R₃ is 3-azabicyclo-[3.3.1]nonan-3-yl, X is hydrogen, R₁ is CH₂COR₄ wherein R₄ is 2-methylphenyl, R₂ is 3-methylphenyl and R₃ is phenyl or X is hydrogen, R₁ is isopropyl, R₃ is phenyl and R₂ is 3 (1 H-tetrazol-5-yl) phenyl.

(b) 1,5 benzadiazepines of formula (II) and more particularly the compounds.

N-phenyl-N'-[2,3,4,5-tetrahydro-2,4-dioxo-1-(1-adamantylmethyl)-5-phenyl-1H-1,5-benzodiazepin-3-yl]urea;

N-[1-(1-Adamantylmethyl)-2,4-dioxo-5-[2-(4-morpholino)ethyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea;

N-1[-(Adamantylmethyl)-2,4,-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-(3-carboxyphenyl)urea;

N-[(1-Adamantylmethyl)-5-[2-(dimethylamino)ethyl]-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea;

(c) the tryptophan peptide derivatives.

[1S-[1α,2β,[S*(S*)],4α]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl) oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid and salts thereof and

(R-(R*,R*))-4-((2-((3-(1H-indol-3-yl)-2-methyl-2-(( (tricyclo(3.3.1.1,3,7)dec-2-yloxy)carbonyl)amino)propyl) amino)-1-phenylethyl)amino)-4-oxobutanoic acid and salts thereof;

(d) N-tert butyl-2-[3[3-(3-chlorophenyl)ureido-2-oxo-5-phenyl-2,3,4,5 tetrahydro-1 H-(1)-benzazepin-1-yl]ethanoic acid amide.

(e) (R)-γ(3,5-dichloro-benzamido]δ-oxo-8-azaspiro[4,5]decane-8-valeric acid (spiroglumide).

[0034] References hereinafter to a CCK-B antagonists (I) also includes where appropriate pharmaceutically acceptable salts and or solvates thereof.

[0035] Particularly useful CCK-B antagonists for use in the treatment of sleep disorders are:

(+) N-phenyl-N'-[2,3,4,5-tetrahydro-2,4-dioxo-1-(1-adamantylmethyl)-5-phenyl-1H-1,5-benzodiazepin-3-yl]urea (compound 1);

(-) N-[1-(1-Adamantylmethyl)-2,4-dioxo-5-[2-(4-morpholino)ethyl]-2,3,4,5-tetrahydro-1 H-1,5-benzodiazepin-3-yl]-N'-phenylurea (compound 2);

N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N'-3-methylphenyl urea (compound 3);

(R-(R*,R*))4-((2-((3-(1H-indol-3-yl)-2-methyl-2-((tricyclo(3,3,1,1,3,7)dec-2yloxy)carbonyl)amino propyl)amino)-1-phenylethyl)amino-4-oxo-butanoic acid meglumine salt (compound 4).

N-1[-(Adamantylmethyl)-2,4,-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-(3-carboxyphenyl)urea (compound 5);

N-[(1-Adamantylmethyl)-5-[2-(dimethylamino)ethyl]-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea (compound 6);

[0036] The ability of the compounds which exhibit CCK-B antagonist activity to influence sleep patterns may be demonstrated by examining EEG parameters in old rats. In these animals the EEG patterns are disturbed. Administration of an effective amount of a CCK-B antagonist to such an animal alters the EEG pattern towards the normal. These effects may be observed using standard procedures such as those described by H.Depoortere et al. Physiology & Behaviour 1993, 54, 785-793.

[0037] Thus CCK-B antagonists may be useful for the treatment of sleep disorders, including Disorders of Initiating and Maintaining Sleep (insomnias), (DIMS) which can arise from psychophysiological causes, as a consequence of psychiatric disorders (particularly related to anxiety), from drugs and alcohol use and abuse (particularly during withdrawal stages), childhood onset DIMS, nocturnal myoclonus and restless legs. and non specific REM disturbance as seen in ageing. Disorders of the Sleep-Wake Schedule which include jet-lag, disorder due to shift work, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24h sleep phase syndrome, disorders due to blindness and those caused by ageing and dementias. Dysfunctions associated with sleep (parasomnias) for example sleep related enuresis.

[0038] According to a further aspect of the invention we provide the treatment of mammal, including man, for sleep disorders which comprises administering an effective amount of a CCK-B antagonist or a pharmaceutically acceptable salt or solvate thereof to the patient.

[0039] It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.

[0040] It will further be appreciated that the amount of the CCK-B antagonist required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 0.01-2000mg per day e.g 0.01-500mg per day.

[0041] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0042] While it is possible that, for use in therapy, the CCK-B antagonist may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.

[0043] The invention thus further provides a pharmaceutical formulation for the treatment of sleep disorders comprising a CCK-B antagonist or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0044] The compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, implant, or rectal administration. Oral administration is preferred.

[0045] Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, accacia, gelatin, sorbitol, tragacanth, hydroxypropyl cellulose, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, hydrogenated vegetable oils, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

[0046] For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.

[0047] The composition according to the invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may be presented in unit dose form in prefilled syringes, vials and ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles,. and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form which may be obtained by freeze drying for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0048] The composition according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0049] The compositions according to the invention may contain between 0.1 - 99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.

[0050] Examples of suitable pharmaceutical formulations for use in the treatment of sleep disorders include those already specifically described in the specifications of the patent applications referred to above.

[0051] For administration in the form of a tablet a convenient formulation is as follows:

Ingredient	mg/tab
CCK-B antagonist	1.00
Povidone K-30	0.11
Microcrystalline Cellulose	142.44
Croscarmellose sodium	6.00
Magnesium Stearate	0.45
Compression weight	150.00mg

[0052] The CCK-B antagonist and Povidone are dissolved in a suitable solvent such as a mixture of acetone and methanol and the resultant solution spray dried using conventional equipment. The resulting powder is blended with the remaining excipients and compressed using 7.5mm normal concave looking. The tablets are coated using conventional methods and equipment. An example of a suitable coating material is Opadry white OY-S-7322 (Colorcon). The above formulation is particularly convenient for use with the CCK-B antagonist - Compound 1.

Pharmacological Activity

[0053] The ability of CCK-B antagonists to effect sleep patterns in old rats was measured by examining the effect of the compound on the EEG pattern using the procedures described by H Depoortere et al. Physiology & Behaviour 1993 54, 785-793. In this test it was found that a single dose i.p. or p.o. of the CCK-B antagonist resulted in an improvement in total sleep time, in both NREM and REM together with being less awake and with a shorter awakening duration. Thus doses of compounds 1 to 6 identified above that resulted in a significant improvement in total sleep time pattern are as follows:

CCK-B Antagonist	Dose
Compound 1	5 µg/kg ip and po
Compound 2	0.5µg/kg ip
Compound 3	5 µg/kg ip
Compound 4	5 µg/kg ip
Compound 5	15 µg/kg ip
Compound 6	0.5 µg/kg ip

Claims

1. The use of a compound having an antagonist activity at the CCK-B receptor in the manufacture of a medicament for the treatment of sleep disorders.

2. Use according to claim 1 wherein the CCK-B receptor antagonist is a 1,4-benzodiazepine derivative, a 1,5-benzodiazepine derivative, a peptide derivative, a 3-phenylureido-azepen-2-one or 3-phenylureido-benzazepin-2-one derivative or an aspartic acid or glutamic acid derivative.

3. Use according to claim 1 or 2 wherein the CCK-B receptor antagonists is a 1,4 benzodiazepine derivative of formula (I).

and N-oxides thereof and pharmaceutically acceptable salts thereof wherein R₁ represents C_1-6 alkyl (optionally substituted by hydroxyl C_1-4 alkoxy, COR₄, CONR₅R₆ or C_3-7 cycloalkyl) or C_3-7 cycloalkyl;

R₄ represents C_1-6 alkoxy or optionally substituted phenyl;

R₅ is methyl or ethyl and R₆ is phenyl or R₅ and R₆ together form a C₄-C₆ alkylene chain, which may be substitued by 1 or 2 alkyl groups;

R₂ represents a substituted or unsubstituted phenyl group wherein the substitutents may be 1 or 2 of halo, C_1-4 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, C_1-4alkylthio or R₇ wherein R₇ is hydroxy, C_1-4 alkoxy, CO₂R₈, NR₈R₉, SO₂NR₈COR₁₀, CONR₈SO₂R₁₀, or R₇ represents a tetrazolyl, carboxamidotetrazolyl, 3-trifluoromethyl-1,2-4-triazolyl or 5-oxo-1,2,4 oxadiazolyl group, which groups may be substituted on one of the nitrogen atoms by a C_1-4alkyl group;

R₈ represents hydrogen or a C_1-4alkyl group;

R₉ independently represents hydrogen or a C_1-4alkyl group or the group SO₂CF₃;

R₁₀ represents C_1-4alkyl;

R₃ represents C_1-6 alkyl, C_3-7 cycloalkyl, phenyl (optionally substituted by halogen), azacycloalkyl or alkyl substituted by an amino, C_1-4 alkylamino, diC_1-4alkylamino, morpholino, pyrrolidino, piperidino, hexamethylene, thiomorpholino or N-methyl piperazino group; X represents hydrogen or halogen.

4. Use according to claims 1 to 3 wherein the CCK-B antagonist is a 1,4-benzodiazepine derivative of formula (I) wherein X is hydrogen, R₁ is methyl, R₂ is 3-methylphenyl or 3-(5 oxo-1,2,4-oxadiazol-3-yl) phenyl and R₃ is phenyl; X is hydrogen. R₁ is methyl, R₂ is 3 methylphenyl and R₃ is 3-azabicyclo-[3.3.1]nonan-3-yl, X is hydrogen, R1 is CH₂COR₄ wherein R₄ is 2-methylphenyl, R₂ is 3-methylphenyl and R₃ is phenyl or X is hydrogen, R₁ is isopropyl, R₃ is phenyl and R₂ is 3 (1H-tetrazol-5-yl) phenyl.

5. Use according to claims 1 or 2 wherein the CCK-B antagonists is a 1,5 benzodiazepine derivative of formula (II)

wherein

R₁₁ represents a phenyl, C_3-7cycloalkyl, C_7-11 bridgedcycloalkyl or C_1-6alkyl group which alkyl group may be substituted by a hydroxy, phenyl, C_1-6alkoxycarbonyl, C_3-7cycloalkyl, or C_7-11 bridgedcycloalkyl group;

R₁₂ represents a phenyl group optionally substituted by 1 or 2 substituents selected from, halogen, C_1-4alkyl, C_1-4alkylthio, cyano, nitro, trifluoromethyl, trifluoromethoxy, (CH₂)nR₁₄ or O(CH₂)pR₁₄ wherein R₁₄ represents hydroxy, C_1-4alkoxy, CO₂R₁₅ or NR₁₆R₁₇; n is zero or 1; p is an integer from 1 to 4;

R₁₃ represents the group AlkNR₁₈R₁₉ or phenyl optionally substituted by 1 or 2 halogen atom;

R₁₅ represents hydrogen or C_1-4alkyl;

R₁₆ represents hydrogen or C_1-4alkyl;

R₁₇ represents hydrogen, C_1-4alkyl, acyl, or C_2-6alkyl substituted by one or more hydroxy, carboxyl and/or amino groups or R₁₆ and R₁₇ together with the nitrogen atom to which they are attached form a 5-7 saturated heterocyclic ring which contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C_1-4alkyl or hydroxy groups.

R₁₈ and R₁₉ independently represent hydrogen, C_1-4alkyl or C_2-6alkyl substituted by one or more hydroxy, carboxyl and/or amino groups or R₁₈ and R₁₉ together with the nitrogen atom to which they are attached represent a 5-7 saturated heterocyclic ring which may contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C_1-4alkyl or hydroxy groups; Alk represents a straight or branched C_2-6alkylene chain optionally substituted by an hydroxyl group;

Y represents hydrogen or 1 or 2 halogen atoms;

and pharmaceutically acceptable salts and or metabolically labile esters.

6. Use according to claim 5 wherein the CCK-B antagonist is a compound selected from:

N-phenyl-N'-[2,3,4,5-tetrahydro-2,4-dioxo-1-(1-adamantylmethyl)-5-phenyl-1H-1,5-benzodiazepin-3-yl]urea;

N-[1-(1-Adamantylmethyl)-2,4-dioxo-5-[2-(4-morpholino)ethyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea;

N-1[-(Adamantylmethyl)-2,4,-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-(3-carboxyphenyl)urea;

N-[(1-Adamantylmethyl)-5-[2-(dimethylamino)ethyl]-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea;

and enantiomers thereof.

7. Use according to claims 1 or 2 wherein the CCK antagonists is a peptide derivative selected from

[1S-[1α,2β,[S*(S*)],4α]-4-[[2-[[3-(1H-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl) oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid and salts thereof and

(R-(R*,R*))-4-((2-((3-(1H-indol-3-yl)-2-methyl-2-(( (tricyclo(3.3.1.1,3,7)dec-2-yloxy)carbonyl)amino)propyl) amino)-1-phenylethyl)amino)-4-oxobutanoic acid and salts thereof;

8. Use according to claims 1 or 2 wherein the CCK-B antagonist is N-tert butyl-2-[3[3-(3-chlorophenyl)ureido-2-oxo-5-phenyl-2,3,4,5 tetrahydro-1H-(1)-benzazepin-1-yl]ethanoic acid amide.

9. Use according to claims 1 or 2 wherein the CCK-B antagonist is (R)-γ(3,5-dichloro-benzamido)δ-oxo-8-azaspiro[4,5]decane-8-valeric acid.

10. The use of (+) N-phenyl-N'-[2,3,4,5-tetrahydro-2,4-dioxo-1-(1-adamantylmethyl)-5-phenyl-1H-1,5-benzodiazepin-3-yl]urea in the manufacture of a medicament for the treatment of sleep disorders.

11. The use of a compound selected from;

(-) N-[1-(1-Adamantylmethyl)-2,4-dioxo-5-[2-(4-morpholino)ethyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea;

N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N'-3-methylphenyl urea;

(R-(R*,R*))4-((2-((3-(1H-indol-3-yl)-2-methyl-2-((tricyclo(3,3,1,1,3,7)dec-2yloxy)carbonyl)amino) propyl)amino)-1-phenylethyl)amino-4-oxo-butanoic acid meglumine salt;

N-1[-(Adamantylmethyl)-2,4,-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-(3-carboxyphenyl)urea;

N-[(1-Adamantylmethyl)-5-[2-(dimethylamino)ethyl]-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea;

in the manufacturing of a medicament for the treatment of sleep disorders.

Ansprüche

1. Verwendung einer Verbindung mit einer antagonistischen Wirkung auf den CCK-B-Rezeptor für die Herstellung eines Medikaments für die Behandlung von Schlafstörungen.

2. Verwendung gemäß Anspruch 1, worin der CCK-B-Rezeptor Antagonist ein 1,4-Benzodiazepinderivat, ein 1,5-Benzodiazepinderivat, ein Peptidderivat, ein 3-Phenylureido-azepen-2-on- oder 3-Phenylureido-benzazepin-2-on-Derivat oder ein Asparginsäure- oder Glutaminsäure-Derivat ist.

3. Verwendung gemäß einem der Ansprüche 1 oder 2, worin der CCK-B-Rezeptor Antagonist ein 1,4-Benzodiazepinderivat der Formel (I)

und N-Oxide davon und pharmazeutisch annehmbare Salze davon ist,
worin R₁ C_1-6 Alkyl (optional substituiert durch Hydroxyl, C_1-4 Alkoxy, COR₄, CONR₅R₆ oder C_3-7 Cycloalkyl) oder C_3-7 Cylcoalkyl darstellt;

R₄ stellt C_1-6 Alkoxy oder optional substituiertes Phenyl dar;

R₅ ist Methyl oder Ethyl und R₆ ist Phenyl oder R₅ und

R₆ bilden zusammen eine C₄-C₆ Alkylenkette, die mit 1 oder 2 Alkylgruppen substituiert sein kann;

R₂ stellt eine substituierte oder unsubstituierte Phenylgruppe dar, worin die Substituenten 1 oder 2 von Halogen, C_1-4 Alkyl, Nitro, Cyano, Trifluormethyl, Trifluormethoxy, C_1-4 Alkylthio oder R₇ sein können, worin R₇ Hydroxy, C_1-4 Alkoxy, CO₂R₈, NR₈R₉, SO₂NR₈COR₁₀, CONR₈SO₂R₁₀ ist, oder R₇ eine Tetrazolyl-, Carboxamidotetrazolyl-, 3-Trifluormethyl-1,2,4-triazolyl oder 5-Oxo-1,2,4-oxadiazolyl-Gruppe darstellt, wobei die Gruppen an einem der Stickstoffatome durch eine C_1-4 Alkylgruppe substituiert sein können;

R₈ stellt Wasserstoff oder eine C_1-4 Alkylgruppe dar;

R₉ stellt unabhängig Wasserstoff oder eine C_1-4 Alkylgruppe oder die Gruppe SO₂CF₃ dar;

R₁₀ stellt C_1-4 Alkyl dar;

R₃ stellt C_1-6 Alkyl, C_3-7 Cycloalkyl, Phenyl (optional substituiert durch Halogen), Azacycloalkyl oder Alkyl substituiert durch eine Amino-, C_1-4 Alkylamino-, di-C_1-4 Alkylamino-, Morpholino-, Pyrrolidino-, Piperidino-, Hexamethylen-, Thiomorpholino- oder N-Methylpiperazino-Gruppe dar; X stellt Wasserstoff oder Halogen dar.

4. Verwendung gemäß Ansprüchen 1 bis 3, worin der CCK-B-Antagonist ein 1,4-Benzodiazepinderivat der Formel (I) ist, worin X Wasserstoff ist, R₁ ist Methyl, R₂ ist 3-Methylphenyl oder 3-(5-Oxo-1,2,4-oxadiazol-3-yl)phenyl und R₃ ist Phenyl; X ist Wasserstoff. R₁ ist Methyl, R₂ ist 3-Methylphenyl und R₃ ist 3-Azabicyclo-[3.3.1]nonan-3-yl, X ist Wasserstoff, R₁ ist CH₂COR₄ worin R₄ 2-Methylphenyl ist, R₂ ist 3-Methylphenyl und R₃ ist Phenyl oder X ist Wasserstoff, R₁ ist Isopropyl, R₃ ist Phenyl und R₂ ist 3-(1H-Tetrazol-5-yl)phenyl.

5. Verwendung gemäß Ansprüchen 1 oder 2, worin der CCK-B-Antagonist ein 1,5-Benzodiazepinderivat der Formel (II) ist:

worin R₁₁ eine Phenyl-, C_3-7 Cycloalkyl-, C_7-11 überbrückte Cycloalkyl- oder C_1-6 Alkylgruppe darstellt, wobei die Alkylgruppe durch eine Hydroxy-, Phenyl-, C_1-6 Alkoxycarbonyl-, C_3-7 Cycloalkyl- oder C_7-11 überbrückte Cycloalkylgruppe substituiert sein kann;

R₁₂ stellt eine Phenylgruppe optional substituiert durch 1 oder 2 Substituenten ausgewählt aus Halogen, C_1-4 Alkyl, C_1-4 Alkylthio, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, (CH₂)nR₁₄ oder O(CH₂)pR₁₄, worin R₁₄ Hydroxy, C_1-4 Alkoxy, CO₂R₁₅ oder NR₁₆R₁₇ darstellt, dar; n ist 0 oder 1; p ist eine ganze Zahl von 1 bis 4; R₁₃ stellt die Gruppe AlkNR₁₈R₁₉ oder optional durch 1 oder 2 Halogenatome substituiertes Phenyl dar;

R₁₅ stellt Wasserstoff oder C_1-4 Alkyl dar;

R₁₆ stellt Wasserstoff oder C_1-4 Alkyl dar;

R₁₇ stellt Wasserstoff, C_1-4 Alkyl, Acyl oder C_2-6 Alkyl substituiert durch eine oder mehrere Hydroxy-, Carboxyl- und/oder Amino-Gruppen dar oder R₁₆ und R₁₇ bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-7 gesättigten heterozyklischen Ring, der ein zusätzliches Heteroatom ausgewählt aus Sauerstoff, Schwefel oder Stickstoff enthalten kann, und/oder durch 1 oder 2 C_1-4 Alkyl- oder Hydroxy-Gruppen substituiert sein kann;

R₁₈ und R₁₉ stellen unabhängig Wasserstoff, C_1-4 Alkyl oder C_2-6 Alkyl substituiert durch eine oder mehrere Hydroxy-, Carboxyl- und/oder Amino-Gruppen dar, oder R₁₈ und R₁₉ stellen zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-7 gesättigten heterozyklischen Ring dar, der ein zusätzliches Heteroatom ausgewählt aus Sauerstoff, Schwefel oder Stickstoff enthalten kann, und/oder durch 1 oder 2 C_1-4 Alkyl- oder Hydroxy-Gruppen substituiert sein kann; Alk stellt eine geradkettige oder verzweigte C_2-6 Alkylenkette optional substituiert durch eine Hydroxylgruppe dar;

Y stellt Wasserstoff oder 1 oder 2 Halogenatome dar;

und pharmazeutisch akzeptable Salze und/oder metabolisch labile Ester.

6. Verwendung gemäß Anspruch 5, worin der CCK-B-Antagonist eine Verbindung ausgewählt aus:

N-Phenyl-N'-[2,3,4,5-tetrahydro-2,4-dioxo-1-(1-adamantylmethyl)-5-phenyl-1H-1,5-benzodiazepin-3-yl]harnstoff;

N-[1-(1-Adamantylmethyl)-2,4-dioxo-5-[2-(4-morpholino)ethyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylharnstoff;

N-1[-(Adamantylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-(3-carboxyphenyl)harnstoff;

N-[(1-Adamantylmethyl)-5-[2-(dimethylamino)ethyl]-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylharnstoff;

und Enantiomeren davon ist.

7. Verwendung gemäß Ansprüchen 1 oder 2, worin der CCK-Antagonist ein Peptidderivat ausgewählt aus:

[1S-[1α,2β,[S*(S*)],4α]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutansäure und Salzen davon und

(R-(R*,R*))-4-((2-((3-(1H-indol-3-yl)-2-methyl-2-(((tricyclo(3.3.1.1,3,7)dec-2-yl-oxy)carbonyl)amino)propyl)amino)-1-phenylethyl)amino)-4-oxobutansäure und Salzen davon ist.

8. Verwendung gemäß Ansprüchen 1 oder 2, worin der CCK-B-Antagonist N-tert-Butyl-2-[3[3-(3-chlorophenyl)ureido-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)-benzazepin-1-yl]ethansäureamid ist.

9. Verwendung gemäß Ansprüchen 1 oder 2, worin der CCK-B-Antagonist (R)-γ(3,5-Dichlor-benzamido)δ-oxo-8-azaspiro[4,5]decan-8-valeriansäure ist.

10. Verwendung von (+) N-Phenyl-N'-[2,3,4,5-tetrahydro-2,4-dioxo-1-(1-adamantylmethyl)-5-phenyl-1H-1,5-benzodiazepin-3-yl]harnstoff für die Herstellung eines Medikaments für die Behandlung von Schlafstörungen.

11. Verwendung einer Verbindung ausgewählt aus:

(-) N-[1-(1-Adamantylmethyl)-2,4-dioxo-5-[2-(4-morpholino)ethyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylharnstoff;

N-[2,3-Dihydro-1-methyl-2-oxo-5-phenyl-lH-1,4-benzodiazepin-3-yl]-N'-3-methylphenylharnstoff; (R-(R*,R*))4-((2-((3-(1H-Indol-3-yl)-2-methyl-2-((tricyclo(3,3,1,1,3,7)dec-2-yl-oxy)carbonyl)amino)propyl)amino)-1-phenylethyl)amino-4-oxo-butansäure Megluminsalz

N-l[-(Adamantylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-(3-carboxyphenyl)harnstoff;

N-[(1-Adamantylmethyl)-5-[2-(dimethylamino)ethyl]-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylharnstoff;

für die Herstellung eines Medikaments für die Behandlung von Schlafstörungen.

Revendications

1. Utilisation d'un composé présentant une activité antagoniste au récepteur CCK-B dans la préparation d'un médicament pour le traitement des troubles du sommeil.

2. Utilisation selon la revendication 1, dans laquelle l'antagoniste du récepteur CCK-B est un dérivé 1,4-benzodiazépine, un dérivé 1,5-benzodiazépine, un dérivé peptidique, un dérivé 3-phényluréido-azépén-2-one ou 3-phényluréido-benzazépin-2-one ou un dérivé d'acide aspartique ou d'acide glutamique.

3. Utilisation selon la revendication 1 ou 2, dans laquelle l'antagoniste du récepteur CCK-B est un dérivé 1,4-benzodiazépine répondant à la formule (I)

et les N-oxydes de celui-ci et les sels pharmaceutiquement acceptables de celui-ci
dans laquelle R₁ représente un groupe alkyle en C_1-6 (facultativement substitué par un groupe hydroxyle, un groupe alcoxy en C_1-4, un groupe COR₄, un groupe CONR₅R₆ ou un groupe cycloalkyle en C_3-7) ou un groupe cycloalkyle en C_3-7 ;

R₄ représente un groupe alcoxy en C_1-6 ou un groupe phényle facultativement substitué ;

R₅ représente un groupe méthyle ou un groupe éthyle et R₆ représente un groupe phényle ou R₅ et R₆ forment ensemble une chaîne alkylène en C_4-6, qui peut être substituée par 1 ou 2 groupes alkyles ;

R₂ représente un groupe phényle substitué ou non-substitué, dans lequel les substituants peuvent représenter 1 ou 2 groupes choisis parmi un atome d'halogène, un groupe alkyle en C_1-4, un groupe nitro, un groupe cyano, un groupe trifluorométhyle, un groupe trifluorométhoxy, un groupe (alkyle en C_1-4)thio ou R₇, où R₇ représente un groupe hydroxyle, un groupe alcoxy en C_1-4, un groupe CO₂R₈, un groupe NR₈R₉, un groupe SO₂NR₈COR₁₀, un groupe CONR₈SO₂R₁₀, ou R₇ représente un groupe tétrazolyle, un groupe carboxamdidotétrazolyle, un groupe 3-trifluorométhyl-1,2,4-triazolyle ou un groupe 5-oxo-1,2,4-oxadiazolyle, ces groupes pouvant être substitués sur un des atomes d'azote par un groupe alkyle en C_1-4;

R₈ représente un atome d'hydrogène ou un groupe alkyle en C_1-4 ;

R₉ représente indépendamment un atome d'hydrogène ou un groupe alkyle en C_1-4 ou le groupe SO₂CF₃ ;

R₁₀ représente un groupe alkyle en C_1-4 ;

R₃ représente un groupe alkyle en C_1-6, un groupe cycloalkyle en C_3-7, un groupe phényle (facultativement substitué par un atome d'halogène), un groupe azacycloalkyle ou un groupe alkyle substitué par un groupe amino, un groupe (alkyle en C_1-4)amino, un groupe di(alkyle en C_1-4)amino, un groupe morpholino, un groupe pyrrolidino, un groupe pipéridino, un groupe hexaméthylène, un groupe thiomorpholino ou un groupe N-méthyl-pipérazino ; X représente un atome d'hydrogène ou un atome d'halogène.

4. Utilisation selon les revendications 1 à 3, dans laquelle l'antagoniste de CCK-B est un dérivé 1,4-benzodiazépine répondant à la formule (I), dans laquelle X représente un atome d'hydrogène, R₁ représente un groupe méthyle, R₂ représente un groupe 3-méthylphényle ou un groupe 3-(5 oxo-1,2,4-oxadiazol-3-yl)phényle et R₃ représente un groupe phényle; X représente un atome d'hydrogène, R₁ représente un groupe méthyle, R₂ représente un groupe 3-méthylphényle et R₃ représente un groupe 3-azabicyclo-[3.3.1]nonan-3-yle; X représente un atome d'hydrogène, R₁ représente un groupe CH₂COR₄, dans lequel R₄ représente un groupe 2-méthylphényle, R₂ représente un groupe 3-méthylphényle et R₃ représente un groupe phényle ou X représente un atome d'hydrogène, R₁ représente un groupe isopropyle, R₃ représente un groupe phényle et R₂ représente un groupe 3-(1H-tétrazol-5-yl)phényle.

5. Utilisation selon les revendications 1 ou 2, dans laquelle l'antagoniste de CCK-B est un dérivé 1,5-benzodiazépine répondant à la formule (II)

dans laquelle

R₁₁ représente un groupe phényle, un groupe cycloalkyle en C_3-7, un groupe cycloalkyle en C_7-11 ponté ou un groupe alkyle en C_1-6, groupe alkyle qui peut être substitué par un groupe hydroxyle, un groupe phényle, un groupe (alcoxy en C_1-6)carbonyle, un groupe cycloalkyle en C_3-7 ou un groupe cycloalkyle en C_7-11 ponté ;

R₁₂ représente un groupe phényle facultativement substitué par 1 ou 2 substituants choisis parmi un atome d'halogène, un groupe alkyle en C_1-4, un groupe (alkyle en C_1-4)thio, un groupe cyano, un groupe nitro, un groupe trifluorométhyle, un groupe trifluorométhoxy, un groupe (CH₂)_nR₁₄ ou un groupe O(CH₂)_pR₁₄, où R₁₄ représente un groupe hydroxyle, un groupe alcoxy en C_1-4, un groupe CO₂R₁₅ ou un groupe NR₁₆R₁₇; n vaut 0 ou 1 ; p représente un nombre entier de 1 à 4 ;

R₁₃ représente le groupe AlkNR₁₈R₁₉ ou un groupe phényle facultativement substitué par 1 ou 2 atomes d'halogène ;

R₁₅ représente un atome d'hydrogène ou un groupe alkyle en C_1-4 ;

R₁₆ représente un atome d'hydrogène ou un groupe alkyle en C_1-4;

R₁₇ représente un atome d'hydrogène, un groupe alkyle en C_1-4, un groupe acyle, ou un groupe alkyle en C_2-6 substitué par un ou plusieurs groupes hydroxyle, carboxyle et/ou amino ou R₁₆ et R₁₇, ensemble avec l'atome d'azote auquel ils sont attachés, forment un noyau hétérocyclique saturé à 5 à 7 membres qui contient un hétéroatome supplémentaire choisi parmi l'oxygène, le soufre ou l'azote et/ou qui peut être substitué par 1 ou 2 groupes alkyle en C_1-4 ou hydroxyle,

R₁₈ et R₁₉ représentent indépendamment un atome d'hydrogène, un groupe alkyle en C_1-4 ou un groupe alkyle en C_2-6 substitué par un ou plusieurs groupes hydroxyle, carboxyle et/ou amino ou R₁₈ et R₁₉, ensemble avec l'atome d'azote auquel ils sont attachés, représentent un noyau hétérocyclique saturée à 5 à 7 membres qui peut contenir un hétéroatome supplémentaire choisi parmi l'oxygène, le soufre ou l'azote et/ou qui peut être substitué par 1 ou 2 groupes alkyle en C_1-4 ou hydroxyle ; Alk représente une chaîne alkylène en C_2-6 linéaire ou ramifiée facultativement substituée par un groupe hydroxyle ;

Y représente un atome d'hydrogène ou 1 ou 2 atomes d'halogène ;

et les sels pharmaceutiquement acceptables et/ou les esters métaboliquement labiles.

6. Utilisation selon la revendication 5, dans laquelle l'antagoniste de CCK-B est un composé choisi parmi :

la N-phényl-N'-[2,3,4,5-tétrahydro-2,4-dioxo-1-(1-adamantylméthyl)-5-phényl-1H-1,5-benzodiazépin-3-yl]urée ;

la N-[1-(1-adamantylméthyl)-2,4-dioxo-5-[2-(4-morpholino)éthyl]-2,3,4,5-tétrahydro-1H-1,5-benzodiazépin-3-yl]-N'-phénylurée ;

la N-1[-(adamantylméthyl)-2,4-dioxo-5-phényl-2,3,4,5-tétrahydro-1H-1,5-benzodiazépin-3-yl]-N'-(3-carboxyphényl)urée ;

la N-[(1-adamantylméthyl)-5-[2-(diméthylamino)éthyl]-2,4-dioxo-2,3,4,5-tétrahydro-1H-1,5-benzodiazépin-3-yl]-N'-phénylurée ;

et les énantiomères de celui-ci.

7. Utilisation selon les revendications 1 ou 2, dans laquelle l'antagoniste de CCK est un dérivé peptidique choisi parmi

l'acide [1S-[1α,2β,[S*(S*)],4α]-4-[[2-[[3-(1H-3-yl)-2-méthyl-1-oxo-2-[[[(1,7,7-triméthylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phényl-éthyl]amino]-4-oxobutanoïque et les sels de celui-ci et

l'acide (R-(R*,R*))-4-((2-((3-(1H-indol-3-yl)-2-méthyl-2-(((tricyclo(3.3.1.1.3.7)-déc-2-yloxy)carbonyl)amino)propyl)amino)-1-phényléthyl)amino)-4-oxo-butanoïque et les sels de celui-ci.

8. Utilisation selon les revendications 1 ou 2, dans laquelle l'antagoniste de CCK-B est l'amide de l'acide N-tert.-butyl-2-[3-[3-(3-chlorophényl)uréido-2-oxo-5-phényl-2,3,4,5-tétrahydro-1H-(1)-benzazépin-1-yl]-éthanoïque.

9. Utilisation selon les revendications 1 ou 2, dans laquelle l'antagoniste de CCK-B est l'acide (R)-γ-(3,5-dichloro-benzamido)-6-oxo-8-aza-spiro[4,5]décane-8-valérique.

10. Utilisation de la (+)-N-phényl-N'-[2,3,4,5-tétrahydro-2,4-dioxo-1-(1-adamantylméthyl)-5-phényl-1H-1,5-benzodiazépin-3yl]urée dans la préparation d'un médicament pour le traitement des troubles du sommeil.

11. Utilisation d'un composé choisi parmi :

la (-)-N-[1-(1-adamantylméthyl)-2,4-dioxo-5-[2-(4-morpholino)éthyl]-2,3,4,5-tétrahydro-1H-1,5-benzodiazépin-3-yl]-N'-phénylurée ;

la N-[2,3-dihydro-1-méthyl-2-oxo-5-phényl-1H-1,4-benzodiazépin-3-yl]-N'-3-méthylphénylurée ;

l'acide (R-(R*,R*))-4-((2-((3-(1H-indol-3-yl)-2-méthyl-2-((tricyclo(3.3.1.1.3.7)-déc-2-yloxy)carbonyl)amino)propyl)amino)-1-phényléthyl)amino-4-oxo-butanoïque, sel de méglumine ;

la N-1[-(adamantylméthyl)-2,4-dioxo-5-phényl-2,3,4,5-tétrahydro-1H-1,5-benzodiazépin-3yl]-N'-(3-carboxyphényl)urée ;

la N-[(1-adamantylméthyl)-5-[2-(diméthylamino)éthyl]-2,4-dioxo-2,3,4,5-tétrahydro-1H-1,5-benzodiazépin-3-yl]-N'-phénylurée ;

dans la préparation d'un médicament pour le traitement des troubles du sommeil.